Since its discovery in the 1950's, synthetic oral progesterone has been used for a variety of gynecological conditions. However, androgenic activity inherent in the synthetic compound precludes its liberal use in assisted reproductive technology (ART) because of the threat of teratogenic effects.
Furthermore, synthetic progesterone used in hormonal replacement therapy (HRT) may partially reverse the estrogenic benefits on the cardiovascular system and lipoprotein metabolism (Lobo, Am. J. Obstet. Gynecol. 166 (1992), 1997-2004; Fahraeus et al., Eur. J. Clin. Invest. 13 (1983), 447-453; Ottosson et al., Am. J. Obstet. Gynecol. 151 (1985), 746-750; Knopp, Am. J. Obstet. Gynecol. 158 (1988), 1630-1643; Crook et al., 166 (1992) 950-954).
Natural progesterone is devoid of any androgenic activity that might compromise lipoprotein metabolism or induce teratogenicity. Moreover, it probably has a direct beneficial effect on blood vessels (Jiang et al., Eur. J. Pharmacol. 211 (1992), 163-167).
The major difficulty in utilizing natural progesterone is its route of administration. Oral intake is hampered by rapid and extensive intestinal and liver metabolism, leading to poorly sustained serum levels and low bioavailability (Adlercreutz et al., J. Steroid Biochem. 13 (1980), 231-244; Arafat et al., Am. J. Obstet. Gynecol. 159 (1988), 1203-1209; Whitehead et al., Brit. Med. J. 280 (1980), 825-827; Ottosson et al., Br. J. Obstet. Gynecol. 91 (1984), 11 11-1 119; Padwick et al., Fertil. Steril. 46 (1986), 402-407; Nahoul et al., Maturitas 16 (1993), 185-202; Nillus et al., Am. J. Obstet. Gynecol. 110 (1971), 470-477; Chakmakjian et al., J. Reprod. Med. 32 (1987), 443-448). Intramuscular injection assures reliable absorption, but is painful, can cause local irritation and cold abscesses (Devroey et al., Int. J. Fertil. 34 (1989), 188-193), must be administered by trained medical personnel, and often suffers from low patient compliance.
For these reasons, the vaginal route has become the most established way in which to deliver natural progesterone. The progesterone is easily administered to the vagina, which has a large potential of absorption, and also avoids liver first-pass metabolism when delivered to the vagina.
Many vaginal formulations have been assayed, mostly as suppositories (Price et al., Fertil. Steril. 39 (1983), 490-493; Norman et al., Fertil. Steril. 56 (1991), 1034-1039; Archer et al., Am. J. Obstet. Gynecol., 173 (1995), 471-478), gelatin capsules (Devroey et al., Int. J. Fertil. 34 (1989), 188-193; Smitz et al;, Hum. Reprod. 2 (1992), 309-314; Miles et al., Fertil. Steril. 62 (1994), 485-490), and recently as bio-adhesive gels (Fanchin et al., Obstet. Gynecol. 90 (1997), 396-401; Ross et al., Am. J. Obstet. Gynecol. 177 (1997), 937-941).
Although the suppositories are easily inserted, they melt at body temperature and lead to disturbing vaginal discharge. Oral gelatin capsule containing micronized progesterone have also been used vaginally (Devroey et al., Int. J. Fertil. 34 (1989), 188-193; Smitz et al., Hum. Reprod. 2 (1992), 309-314; Miles et al., Fertil. Steril. 62 (1994), 485-490), but insertion of a small capsule high into the vagina is difficult and large doses of 600 to 800 mg are needed to achieve adequate plasma concentration (Smitz et al., Hum. Reprod. 2 (1992), 309-314; Miles et al., Fertil. Steril. 62 (1994), 485-490; Bourgain et al., Hum. Reprod. 5 (1990), 537-543).
U.S. Pat. Nos. 5,084,277 and 5,116,619, both to Greco et al., disclose a process for the preparation of a progesterone-containing tablet and tablets so prepared. The Greco et al. process involves wet granulation of progesterone into the tablets. As is well-known in the art, wet granulation processes necessitate several steps in the formulation of the resulting tablets. These steps add considerably to the production costs of tablets produced by wet granulation methods, particularly in comparison to comparable “direct compaction” methods, in which the material of interest is tabletted while dry and which involve fewer steps than wet-granulation methods. Greco et al. employs a wet granulation technique because commercially available progesterone has bulk properties which render it unsuitable for direct compaction in the concentrations necessary for use in ART (typically about 50-100 mg progesterone per 1000 mg tablet). Greco gives no suggestion as to how one might be able to tablet progesterone via a direct-compaction method, which is economically more desirable.
The use of a wet granulation method in the preparation of progesterone-containing tablets also precludes incorporation of an effervescent into the tablet. If the tablet is to be vaginally administered, incorporation of an effervescent would be helpful, since the effervescent would aid in the dissolution of the tablet and absorption of the progesterone into the bloodstream.